Differential Brain, Cognitive and Motor Profiles Associated with Partial Trisomy. Modeling Down Syndrome in Mice
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We hypothesize that the trisomy 21 (Down syndrome) is the additive and interactive outcome of the triple copy of different regions of HSA21. Because of the small number of patients with partial trisomy 21, we addressed the question in the Mouse in which three chromosomal regions located on MMU10, MMU17 and MMU16 carries almost all the HSA21 homologs. Male mice from four segmental trisomic strains covering the D21S17-ETS2 (syntenic to MMU16) were examined with an exhaustive battery of cognitive tests, motor tasks and MRI and compared with TS65Dn that encompasses D21S17-ETS2. None of the four strains gather all the impairments (measured by the effect size) of TS65Dn strain. The 152F7 strain was close to TS65Dn for motor behavior and reference memory and the three other strains 230E8, 141G6 and 285E6 for working memory. Episodic memory was impaired only in strain 285E6. The hippocampus and cerebellum reduced sizes that were seen in all the strains indicate that trisomy 21 is not only a hippocampus syndrome but that it results from abnormal interactions between the two structures.
KeywordsTrisomy 21 D21S17-ETS2 region MRI Protein–protein interactions Effect size Cognition
We thank INSERM U 910 “Génétique Médicale, Génomique Fonctionnelle”, CNRS UMR 7290 Psychologie cognitive, Fédération de Recherche 3C–Comportement Cerveau–Cognition, and Aix Marseille University, and also the Fondation Jérôme Lejeune. AFI-Aveyron provided invaluable assistance with computer software for the MWM analysis and the Cavalieri stereology method. We wish to express our gratitude to the European Mouse Mutant Archive (EMMA) for the generous gift of two strains of segmental trisomic mice. Maire-Laure Dessain (UPS 44 TAAM, CNRS) genotyped the mice. Our special thanks to the anonymous reviewers of the first version of the manuscript and to Doctor Henri Bléhaut for his scientific support.
Conceived and designed the experiments: P-L Roubertoux, M. Carlier, S. Tordjman. Behavioral assessment of the mice: P-L Roubertoux, A. Ghata, C. Bartoli, M. Carlier. MRI: N Baril. P. Cau, P-L. Roubertoux. Data analysis : P-L Roubertoux, M Carlier. Molecular analysis: J. di Christofaro, P Bourgeois, P-L Roubertoux. Mouse breeding: C. Scajola. Wrote the paper: P-L Roubertoux, M Carlier. All the authors reviewed the manuscript for intellectual content and approved submission.
Compliance with Ethical Standards
Conflict of interest
Pierre L. Roubertoux, Nathalie Baril, Pierre Cau, Christophe Scajola, Adeline Ghata, Catherine Bartoli, Patrice Bourgeois, Julie di Christofaro, Sylvie Tordjman, Michèle Carlier declare that they have no conflict of interests.
The protocols for the present study were approved by the Comité d’éthique pour l’expérimentation animale n°14, under the title “Rôle de la région D21517-ET52 (MMU 16) dans les dysfonctions cérébrales de souris modèles du syndrome de Down,” with PL Roubertoux as the main investigator (reference number 23- 23092012, dated October 11, 2012).
- Belichenko NP, Belichenko PV, Kleschevnikov AM, Salehi A, Reeves RH, Mobley WC (2009) The “Down syndrome critical region” is sufficient in the mouse model to confer behavioral, neurophysiological, and synaptic phenotypes characteristic of Down syndrome. J neurosci 29:5938–5948CrossRefPubMedPubMedCentralGoogle Scholar
- Carlier M, Desplanches AG, Philip N, Stefanini S, Vicari S, Volterra V, Deruelle C, Fisch G, Doyen AL, Swillen A (2011) Laterality preference and cognition: cross-syndrome comparison of patients with trisomy 21 (Down), del7q11.23 (Williams-Beuren) and del22q11.2 (DiGeorge or Velo-Cardio-Facial) syndromes. Behav Genet 41:413–422CrossRefPubMedGoogle Scholar
- Caubit X, Gubellini P, Andrieux J, Roubertoux PL, Metwaly M, Jacq B, Fatmi A, Had-Aissouni L, Kwan KY, Salin P et al. (2016). TSHZ3 deletion causes an autism syndrome and defects in cortical projection neurons. Nat GenetGoogle Scholar
- Cohen J (1988) Statistical power analysis for the behavioral sciences. Lawrence Earlbaum Associates., Hillsdale, NJGoogle Scholar
- Delabar JM, Theophile D, Rahmani Z, Chettouh Z, Blouin JL, Prieur M, Noel B, Sinet PM (1993). Molecular mapping of twenty-four features of Down syndrome on chromosome 21. Eur J Human Genet 1:114–124.Google Scholar
- Field A (2005) Discovering statistics using SPSS. SAGE, LondonGoogle Scholar
- Lipp HP, Wahlsten D (1992) Absence of corpus callosum. In: Driscoll P (ed) Genetically defined animal models of neurological disorders. Birkhauser, Boston, pp 152–174Google Scholar
- Lyle R, Bena F, Gagos S, Gehrig C, Lopez G, Schinzel A, Lespinasse J, Bottani A, Dahoun S, Taine L, et al. (2009). Genotype-phenotype correlations in Down syndrome identified by array CGH in 30 cases of partial trisomy and partial monosomy chromosome 21. Eur J Human Genet 17:454–466.CrossRefGoogle Scholar
- Palkovits M, Brownstein MJ (1988). Maps and guide to microdissection of the rat brain New York, Elsevier.Google Scholar
- Paxinos G, Franklin KBJ (2004). The mouse brain in stereotaxic coordinates, Compact. 2nd edn. Elsevier Academic Press, AmsterdamGoogle Scholar
- Pereira PL, Magnol L, Sahun I, Brault V, Duchon A, Prandini P, Gruart A, Bizot JC, Chadefaux-Vekemans B, Deutsch S, et al. (2009). A new mouse model for the trisomy of the Abcg1-U2af1 region reveals the complexity of the combinatorial genetic code of down syndrome. Human Mol Genet 18:4756–4769.CrossRefGoogle Scholar
- Smith DJ, Stevens ME, Sudanagunta SP, Bronson RT, Makhinson M, Watabe AM, O’Dell TJ, Fung J, Weier HU, Cheng JF et al (1997) Functional screening of 2 Mb of human chromosome 21q22.2 in transgenic mice implicates minibrain in learning defects associated with Down syndrome. Nat Genet 16:28–36CrossRefPubMedGoogle Scholar
- Wehner, JM, Radcliffe, RA (2004). Cued and contextual fear conditioning in mice. Current protocols in neuroscience / editorial board, Jacqueline N Crawley [et al] Chap. 8, Unit 8 5 C.Google Scholar
- Yu T, Li Z, Jia Z, Clapcote SJ, Liu C, Li S, Asrar S, Pao A, Chen R, Fan N, et al. (2010a). A mouse model of Down syndrome trisomic for all human chromosome 21 syntenic regions. Human Mol Genet 19:2780–2791.Google Scholar
- Yu T, Liu C, Belichenko P, Clapcote SJ, Li S, Pao A, Kleschevnikov A, Bechard AR, Asrar S, Chen R et al (2010b) Effects of individual segmental trisomies of human chromosome 21 syntenic regions on hippocampal long-term potentiation and cognitive behaviors in mice. Brain Res 1366:162–171Google Scholar
- Zhang L, Meng K, Jiang X, Liu C, Pao A, Belichenko PV, Kleschevnikov AM, Josselyn S, Liang P, Ye P, et al. (2014). Human chromosome 21 orthologous region on mouse chromosome 17 is a major determinant of Down syndrome-related developmental cognitive deficits. Human Mol Genet 23:578–589.CrossRefGoogle Scholar